J. Am. Chem. SOC.1994,116, 6455-6456
Lewis Acid-Promoted Diastereoselective Radical Cyclization Using Chiral a&Unsaturated Esters Mayumi Nishida,' Eiji Ueyama, Hiroshi Hayashi, Yoshihito Ohtake, Yousuke Yamaura, Emi Yanaginuma, Osamu Yonemitsu, Atsushi Nishida,'.' and Norio Kawaharal
Faculty of Pharmaceutical Sciences Hokkaido University, Sapporo 060, Japan Hokkaido Institute of Pharmaceutical Sciences Katsuraoka 7-1, Otaru 047-02, Japan
6455
respect to the O=C-C=C bond is important to achieve good diastereoselectivity in radical addition (Figure 1). In contrast to the amide auxiliary the conformation of the ester group exists as an equilibrium mixture of s-cis and s-trans isomers.3J2 Radical cyclization of (-)-8-phenylmenthyl @)-2-octen-7-ynoate ( l ) 1 3 and (-)-8-phenylmenthyl (E)-Znonen-8-ynoate (2)13under the conditions reported by Oshima and Utimoto (1 or 2, 90 mM; n-BusSnH, 1.5 equiv; Et,B, 1.1 equiv; toluene, 0 "C, under Ar)l4 afforded (2-methylenecyclopenty1)acetate 5 and (Zmethylenecyclohexy1)acetate 6, respectively, in good yield. However, only modest diastereoselectivity was observed (Table 1, runs 1 and 9.15
Received March 7, 1994 Radical reactions have become important tools for organic synthesk2 The generation of new stereo centers using chiral auxiliaries in radical C-C bond formation is of much interest in free radical chemistry,3 and high a! and p selectivities4 have been achie~ed.~,~."J Although fl addition of carbon radicals to the a,@unsaturated carbonyl system in an inter- or intramolecularmanner has been widely employed in organic synthesis, stereocontrol in the radical addition to chiral alkenes with &attached chiral auxiliaries remains a challenging issue. Recently, Curran introduced a new imide auxiliarywhich controls the conformation of the O=C-C=C group and the direction of entering radicals, resulting in high B stereoselectivity.' However, several steps are required for the preparation of the auxiliary. Therefore, the development of general and convenient strategies to achieve high degrees of 0diastereoselectivityis still required! We report here that the intramolecular addition of alkenyl radicals to the fl position of 8-phenylmenthyl a!,fl-unsaturated esters showed good to excellent diastereoselectivity in the presence of a Lewis acid. 8-Phenylmenthylalcohol has been widely employed as a chiral auxiliary in diastereoselective reactions.%l1 In addition to the shielding of the *-face of alkenes, the rotamer distribution with (1) Hokkaido Institute of Pharmaceutical Sciences. (2)(a) Giese, B. Radicals in Organic Synthesis: Formation of CarbonCarbonBonds;Pergamon Press: New York, 1986.(b) Curran, D. P. Synthesis 1988,417,489. (c) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.Chem. Rev. 1991, 91,1237. (3) Review: Portcr,N. A.;Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24,296 and references cited therein. (4)For categories of diastereoselective radical reactions, see ref 3. ( 5 ) (a) Porter, N. A.; Lacher, B.; Chang, V. H.-T.; Magnin, D. R. J. Am. Chem. Soc. 1989,llI , 8309.(b) Porter, N. A.; Swann, E Nally, J.; McPhail, A. T. J. Am. Chem. Soc. 1990,112,6740.(c) Porter, N. A.; Scott, D. M.; Rosenstein, I. J.; Giese, B.; Veit, A,; Zeitz, H. G. J. Am. Chem. Soc. 1991, 113, 1791. (d) Porter, N. A.; Bruhnke, J. D.; Wu, W.-X.; Rosenstein, I. J.; Breyer, R. A. J. Am. Chem.Soc. 1991,113,7788.(e)Porter,N.A.;Rosenstein, I. J.; Breyer, R. A.; Bruhnke, J. D.; Wu, W.-X.; McPhail, A. T. J. Am. Chem. Soc. 1992,114,1664.
(6)Curran, D. P.; Shen, W.; Zhang, J.; Heffner, T. A. J. Am. Chem. Soc. 1990,112,6738. (7) (a) Stack, J. G.; Curran, D. P.; Rebek, J., Jr.; Ballcater, P. J. Am. Chem. Soc. 1991, 113, 5918. (b) Stack, J. G.; Curran, D. P.; Geib, S.V.; Rebek, J., Jr.; Ballester, P. J. Am. Chem. Soc. 1992,114, 7007. (8) (a) Reaction using chiral enamine: Renaud, P.; Schubert, S. Synletf 1990,624.(b) Radical addition to enolate of chiral amide: Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169. (c) Reaction of dimethylaluminum chloride with chiral a,@-unsaturated N-acyloxazolidinones: Riick, K.; Kunz, H. Angew. Chem.. In?. Ed. Engl. 1991,30,694.Riick, K.;Kunz, H. Synlett 1992,343.Riick, K.; Kunz, H. Synthesis 1993,1018. (9)Review of diastereoselectivereactions using the 8-phenylmenthylgroup as a chiral auxiliary: Whitesell, J. K. Chem. Reu. 1992,92,953. (10)pSelective radical reactions using the 8-phenylmenthyl group as an auxiliary: (a) Crich, D.; Davies, J. W. TetrahedronLett. 1987,28,4205.(b) Hamon, D.P. G.; Razzino, P.; Massy-Westropp, R. A. J. Chem. Soc.. Chem. Commun.1991,332.(c) Hamon, D. P.G.; Massy-Westropp, R. A. ;Razzino, P. J. Chem. Sa.,Chem. Commun. 1991,722.(d) Chen, M.-Y.; Fang, J.-M.; Tsai, Y.-M.; Yeh, R.-L. J. Chem. Soc., Chem. Commun. 1991, 1603. (e) Snider, B. B.; Zhang, Q.Tetrahedron Left. 1992,33, 5921.( f ) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.;Peisach, D.; Foxman, B. M.;Snider, B. B. J. Org. Chem. 1993.58,7640. (1 1) A previous attempt at @-selectiveradical cyclization using [[(8phenylmenthyl)oxy]carbonyl]ethylene as a radical acceptor: Hart, D. J.; Tsai, Y.-M. J. Am. Chem. Soc. 1984,106,8209.
0002-7863/94/ 1516-6455$04.50/0
&COOR* )n
&COOR* In
( 1 3 - 5 : n=l (R)-6 : n=2
(SI-5 : n=l (SI-6 : n=2 SnBu
L
i
O
O
R
.
COOR'
It has been reported that acrylate is fixed in the s-trans conformation in the presence of a Lewis acid.12 Thus, a suitable Lewis acid capable of surviving under the radical conditionsls would allow reaction to occur predominantly from the s-trans conformer. Addition of BFrOEt2 to the reaction under argon clearly accelerated the cyclization of 1 and 2 and increased the proportion of (R)-isomer in the product (runs 2 and 3,6 and 7). Diastereoselectivities of the radical cyclization of 1 and 2 were 76:24 and 86:14, respectively, in the presence of a high (12)(a) Oppolzer, W.; Kurth, M.; ReichlicD.; Chapuis, C.; Mohnhaupt, M.; Moffatt, F.; Heluetica Chem. Acta 1981,64,2802.(b) Loncharich, R. J.; Schwartz, T. R.; Houk, K. N. J.Am. Chem.Soc. 1987,109,14and references Piyasena, H. P.; Loncharich, R. cited therein. (c) Curran, D. P.; Kim, B. H.; J.; Houk, K. N. J. Org. Chem. 1987,52,2137. (13) Thechiral esters 1 4were prepared by olefinationof 8-phenylmenthyl (triphenylphoshorany1idene)acetateand the correspondingaldehydes. Details of the synthesu, are described in the supplementary material. (14)Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,109,
2547. (15) Diastereoselectivitywas determined by 'H NMR. The configurations of the major diastereoisomers, (R)-5and (R)-6,were determined by chemical conversion to known chiral compounds: A diastereo mixture of 5 (RS = 1.41) was converted to (5')-2-~ndecylcyclopentanone[[cY]D" = +12.8' (c 0.99,ether)]. [Enantiomerically pure (5')-2-~ndecylcyclopentanone: [a]D = +84.2O (~0.83,ether)~6.1 Adiastereomutureof6(RS= 3.3:l) wasconverted to (R)-2-acetonylcyclohexanone[[a]DM* +11.4O (c 4.37,methanol)] [(It)2-Acetonylcyclohexanoneof 80%ee: [a]r,= +23.5' (c6,methanol).1'] Details of these transformations are also described in the supplementary material. (16)Nishida, M.; Nakaoka, K.; Ono, S.;Yonemitsu, 0.; Nishida, A.; Kawahara, N.; Takayanagi, H. J. Org. Chem. 1993,58,5870. (17)Meyers,A. I.; Wi1liams.D. R.;Erickson,G. W.; White,S.; Druelinger, M. J. Am. Chem. Soc. 1981,103,3081. (1 8) Diastermlective radical reactions influenced by Lewis acid: (a) Guindon, Y.; Lavallb, J.-F.; Llinas-Brunet, M.; Homer, G.; Rancourt, J. J. Am. Chem. Soc. 1991,113,9701.(b) Renaud, P.; Ribezzo, M. J. Am. Chem. Soc. 1991,113,7803.(c) Newcomb, M.; Ha, C. TetrahedronLett. 1991.32, 6493.(d) Yamamoto, Y.; Onuki, S.;Yumoto, M.; Asao, N. J. Am. Chem. Soc. 1994,116,421.
0 1994 American Chemical Society
Communications to the Editor
6456 J . Am. Chem. SOC.,Vol. 116, No. 14, 1994 Table 1. Lewis Acid-Promoted Diastereoselective Radical Cyclization run
substrate
n-Bu3SnH (equiv)
Lewis acid
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 1 3 3
1.5 1.5
none BFyOEt2 BFyOEt2 BFyOEt2 none BFj.OEt2 BFyOEt2 BFyOEtz MepAl EtnAl i-Bu3AI Me2AICl EtZAICl EtAlC12 i-BupAl i-Bu3Al none BFyOEt2 i-BupAl MAW none BFyOEt2 MAW
4.5 4.5 1.5 1.5 4.5 2.5 1.5 1.5 1.5 1.5 1.5
1.5 1 .5 1.5 1.5 2.5 1.5 1.5 1.5 4.5 1.5
3 3 4 4 4
[MI 0.72 2.90 2.90 0.72 2.90 1.45 0.36 0.45 0.36 0.25 0.36 0.18 0.36 0.36 1.44 0.36 0.36 2.90 0.36
temp ("C)
time (h)
product
yield (96)
ratiob (RS)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 -40 -78 -78 -78 -78 0 0 -78
4.5 1.5 2.0 0.5 7.0 3.5 1.5 20 min 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1 .o 0.5 20 min 20 min 10 min 10 min 0.8
5 5 5 5
88' 9oC 6oC 90 78' 8oC 394 77 83 76 72 78 73 53e 60 5Or 92 86 83 79 41h 82 42'
58:42 72:28 76:24 76:24 58:42 81:19 86:14 84:16 79:21 85:15 87:13 79:21 83:17 76:24 81:19 81:19 67:33 94:6 9010 96:4 57:43 9010 98:2
6 6 6 6 6 6 6 6 6 6 5 5 5 5
5 5
6 6 6
Concentration of the substrate: 0.09 M. The ratio was determined by 'H N M R . The reactions were carried out under argon. 53% of 2 was recovered. e 16% of 2was recovered. f7was obtained in 11% yield. g Methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide). 41Wof8was isolated. 42% of 8 was isolated. 1
t
H'
(a-5
t H+ (Rb5
Figure 1. Diastereoselective radical cyclization of 1.
concentration of BFyOEt2.19 High concentrations of the Lewis acid appear to be necessary to suppress reaction of the uncomplexed substrate. Although triethylborane can work as a radical initiator under an argon atmosphere, the reaction under dry air proceeded faster with no decrease in the diastereoselectivity(runs 4 and 8). Therefore, the other results presented in Table 1 were obtained under aerobic conditions.20 After surveying other Lewis acids,2' we found that aluminum reagents are effective at lower concentrations of the Lewis acid (runs 9-14). The bulkiness of the alkyl groups on the aluminum reagents affected the diastereoselectivity, and the cyclization of 2 in the presence of (i-Bu),Al afforded the product mixture in (19)Even under conditions using a high concentration of BF+OEtz, the reaction appeared to proceed ula a radical mechanism. Without n-BulSnH or EtaB, no reaction was observed. (20)Representative procedure (run 4 in Table 1): To a solution of 1 (70.5 mg, 0.20mmol) in toluene (2mL) was added BF,-OEtz (807pL, 6.4mmol), Et3B (1.0 M n-hexane solution, 0.21 mL, 0.21 mmol), and n-Bu3SnH (242 pL, 0.9 mmol) in sequence at 0 OC under dry air. The mixture was stirred for 0.5 h and was quenched by addition of a solution of sodium bicarbonate. The usual workup, followed by silica gel column chromatography, afforded a diastereo mixture of 5 (64mg, 90%, R S = 76:24).Destannylation occurred from the initial cyclized products under these conditions.
72% yield and in 87:13 selectivity (run 11). The same Lewis acid was also effective in the cyclization of 1 (81:19, run 15). Performing the reaction at a lower temperature (-40"C) did not improve the selectivity,and the stannylated product 7 was isolated in 11% yield as a single diastereomer (run 16).22 To circumvent the difficulties involved in the selective generation of alkenyl radicals from acetylenic substrates at low temperatures, we next examined the radical reaction of vinyl iodides 3 and 4. The cyclization of 3 proceeded smoothly at -78 OC without Lewis acid, and the selectivity was slightly better (92%, 67:33,run 17) compared to cyclization at 0 OC. Significantly higher selectivitywas observed in the presence of the Lewis acids BFyEt20 (94:6,run 18). (i-Bu)pAl (90:10,run 19), and methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide)23 (MAD, 96:4,run 20). Although six-membered-ring formation using 4 without Lewis acid was inefficient (41%, 57:43,run 2l)>4 cyclization in the presence of BFyEt20 proceeded efficiently and with high diastereoselectivity (82%, 9O:lO) even at 0 "C (run 22). The highest diastereoselectivity was recorded at -78 OC in the presence of MAD (98:2,run 23), although a considerable amount of the side product 8 was obtained. In conclusion,we have reported here an efficient and convenient diastereoselectiveradical cyclization which shows a high degree of 0 selectivity. The presence of a suitable Lewis acid is essential to achieve a high level of selectivity. Supplementary Material Available: Syntheses of 1 4 , representative experiments (runs 4, 8, 20, and 23 in Table l), and chemical conversions of 5 and 6 (8 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. (21)Other Lewis acids were investigated. No effect on the reaction was observed in the presence of Zn(OTf)z, Sn(OTf)z, and MgBq because of their insolubility in the reaction media; TMSOTf and T i c 4 inhibited the reaction by consuming the tin reagent and triethylborane. (22)The stereochemistry of 7 was tentatively assigned as shown on the basis of the transition-state model. (23)Maruoka, K.;Itoh, T.; Sakurai, M.; Nonoshita, K.;Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 3588. (24)Product 8 was isolated in 41% yield which would be formed ula hydrostannation of the triple bond followed by destannylation.
